%0 Journal Article
%A Kim, Minjee
%A Laramy, Janice K
%A Mohammad, Afroz S.
%A Talele, Surabhi
%A Fisher, James
%A Sarkaria, Jann N.
%A Elmquist, William F.
%T Brain distribution of a panel of EGFR inhibitors using cassette-dosing in wild-type and Abcb1/Abcg2 deficient mice
%D 2019
%R 10.1124/dmd.118.084210
%J Drug Metabolism and Disposition
%P dmd.118.084210
%X Tyrosine kinase inhibitors that target the epidermal growth factor receptor (EGFR) have had success in treating EGFR positive tumors, including non-small cell lung cancer (NSCLC). However, developing EGFR inhibitors that can be delivered to the brain remains a challenge. To identify optimal compounds for brain delivery, a panel of EGFR inhibitors was evaluated for distributional kinetics using cassette dosing with the ultimate goal of understanding the brain penetrability of compounds that share the same molecular target in an important oncogenic signaling pathway for both primary brain tumors (glioblastoma) and brain metastases (e.g., NSCLC). Cassette dosing was validated by comparing the brain-to-plasma ratios obtained from cassette dosing to discrete dosing studies. The brain to blood partition coefficients (Kp,brain) were calculated following cassette dosing of the 8 EGFR inhibitors. The comparison of Kp,brain in wild-type and transporter-deficient mice confirmed that two major efflux transporters at the BBB, p-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp), play a crucial role in the brain distribution of 7 out of 8 EGFR inhibitors. Results show that the prediction of brain distribution based on physicochemical properties of a drug can be misleading, especially for compounds subject to extensive efflux transport. Moreover, this study informs the choice of EGFR inhibitors, i.e., determining BBB permeability combined with a known target potency, that may be effective in future clinical trials for brain tumors.
%U http://dmd.aspetjournals.org/content/dmd/early/2019/01/31/dmd.118.084210.full.pdf